Migraine Treatment (s) of the Month: Old Drugs, New Tricks
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Although over the last 3+ decades we have witnessed a revolution in migraine therapeutics, not much new in the way of treatment for acute migraine headache has arrived on the scene since the emergence of the “gepants” (rimegepant/Nurtec, ubrogepant/Ubrelvy, zavgepant/Zavzpret) about 6 years ago. Oral Nurtec and Ubrelvy were the “migraine treatments of the month” for the Spring 2020 and Fall 2020 issues of Migraineur magazine and intranasal Zavzpret for the Spring 2023 issue.
Now we have available to us 3 relatively old drugs, one a compound containing 2 of the 3 oldsters, that are available in what amount to new formulations: Symbravo was FDA-approved for acute migraine headache in January 2025, and Brekiya was approved in May.
We tend to designate sumatriptan (Imitrex) as being the first “designer drug” for migraine treatment (“designer drug“ in that it was developed specifically for the treatment of migraine and not serendipitously found to be effective for migraine after initially being used for another medical indication.). Sumatriptan first became available in the US in a subcutaneously self-administered injectable formulation in 1992. In fact, the first designer drug for migraine was not sumatriptan but was instead dihydroergotamine (DHE), first approved for use in migraine almost 50 years earlier, in 1946.
Although DHE has never been available as an oral therapy, it has been widely used in emergency rooms, hospitals and in-clinic infusion centers as an intravenous therapy for acute, severe migraine headache that has resisted self-administered treatment. That said, one study published in 1996 demonstrated subcutaneously administered DHE to be of similar effectiveness when compared with subcutaneously administered sumatriptan, with the somewhat more rapid onset of relief associated with sumatriptan offset by a much lower rate of early headache recurrence with DHE. Many headache specialists have instructed their patients in the use of subcutaneous administration of DHE via ampule and syringe to treat their most severe migraine headaches, but the lack of a DHE auto-injector typically has led healthcare providers to prescribe the more convenient alternative of sumatriptan administered subcutaneously via a tested and approved auto-injector.
Some years ago my colleagues and I worked in an effort to develop a formulation of DHE administered via its own designated auto-injector, and the large scale clinical trial we conducted showed the drug to be sufficiently effective to justify submission to the FDA for approval of use in the treatment of acute migraine. DHE can be considered a “cousin” of sumatriptan in that the two drugs act upon specific receptors within the migraine’s biologic circuitry to stop the conduction of head pain signal. DHE is somewhat less selective than sumatriptan, however, interacting at other receptor sites as well, and DHE is more likely than sumatriptan to cause nausea as a side effect. Because in our study DHE did not achieve the secondary end point of reduction in migraine-associated nausea at the two hour mark following injection, the FDA voted to withhold approval (an arguably poor decision that for some years thereafter denied migraineurs this appealing option for self-administered treatment of their most severe migraine headaches).
In May the FDA approved Brekiya, a formulation of DHE which may be self-administered via auto injector. Old drug,..but a most welcome new trick. Especially for those migraineurs who require a “rescue” medication for acute, severe migraine headaches and have found subcutaneously injectable sumatriptan to be ineffective - or effective but associated with a high frequency of early headache recurrence - Brekiya represents an attractive new alternative.
One of the 5 “fast-onset” oral triptans and a close molecular cousin of sumatriptan, rizatriptan (Maxalt) was FDA-approved for treatment of acute migraine headache in 1998. As our experience with the oral triptans expanded, we found that taking a non-steroidal anti-inflammatory drug (NSAID) concomitant with the triptan appeared to amplify the triptan’s effectiveness. Naproxen sodium has been the NSAID most commonly studied for this purpose, and there is available a compound oral medication that initially was released under the brand-name Treximet that combines a specially engineered formulation of naproxen sodium and a particularly fast-acting formulation of oral sumatriptan.
And now we have Symbravo, a combination of rizatriptan with meloxicam, another NSAID that has been around for a long time. Long used for conditions such as arthritic pain, meloxicam alone is not a particularly fast-onset medication and thus not especially suitable for acute migraine treatment. In Symbravo, however, meloxicam may join with rizatriptan to exert a rapid therapeutic effect, and with its longer half-life in the body meloxicam remains as a defense against recurrent headache after rizatriptan has been metabolized and departed. Symbravo is not as likely to be as effective as injectable sumatriptan or Brekiya for “rescue” from a rapidly escalating or already severe migraine headache, but it will be a welcome addition to those medications that we use to terminate migraine when the headache is in its earlier stages.
Countering in part the addition of these 2 therapies to our arsenal of pharmaceutical weapons for acute migraine treatment, the company possessing the rights to Reyvow (lasmiditan) has made a financial decision to no longer manufacture the drug. Too bad. Reyvow is an an oral medication with a clever and unique mechanism of action which lacked the potential for producing symptomatic constriction of blood vessels (a rare but more than theoretical potential action of the triptans and DHE).
So it is; therapies for migraine come and go, and those that go typically do so as a consequence of low patient utilization that yields an unattractive financial bottom line.
The revolution in migraine therapeutics continues, and even with some therapies dropping by the wayside there is an ongoing net gain in the number of treatment options available to the migraine population. First the triptans and then the anti-CGRP drugs have made especially large impacts, and peering at the tea leaves that float upon the sea of ongoing clinical research, I predict the arrival of an equally impactful new class of medications for migraine within the next 3 to 5 years. Stay tuned.
JFR
